NF-Y Subunits Overexpression in HNSCC.

Abstract

Simple SummaryCancer cells have altered gene expression profiles. This is ultimately elicited by altered structure, expression or binding of transcription factors to regulatory regions of genomes. The CCAAT-binding trimer is a pioneer transcription factor involved in the activation of “cancer” genes. We and others have shown that the regulatory NF-YA subunit is overexpressed in epithelial cancers. Here, we examined large datasets of bulk gene expression profiles, as well as single-cell data, in head and neck squamous cell carcinomas by bioinformatic methods. We partitioned tumors according to molecular subtypes, mutations and positivity for HPV. We came to the conclusion that high levels of the histone-like subunits and the “short” NF-YAs isoform are protective in HPV-positive tumors. On the other hand, high levels of the “long” NF-YAl were found in the recently identified aggressive and metastasis-prone cell population undergoing partial epithelial to mesenchymal transition, p-EMT.NF-Y is the CCAAT-binding trimer formed by the histone fold domain (HFD), NF-YB/NF-YC and NF-YA. The CCAAT box is generally prevalent in promoters of “cancer” genes. We reported the overexpression of NF-YA in BRCA, LUAD and LUSC, and of all subunits in HCC. Altered splicing of NF-YA was found in breast and lung cancer. We analyzed RNA-seq datasets of TCGA and cell lines of head and neck squamous cell carcinomas (HNSCC). We partitioned all TCGA data into four subtypes, deconvoluted single-cell RNA-seq of tumors and derived survival curves. The CCAAT box was enriched in the promoters of overexpressed genes. The “short” NF-YAs was overexpressed in all subtypes and the “long” NF-YAl in Mesenchymal. The HFD subunits are overexpressed, except Basal (NF-YB) and Atypical (NF-YC); NF-YAl is increased in p53 mutated tumors. In HPV-positive tumors, high levels of NF-YAs, p16 and ΔNp63 correlate with better prognosis. Deconvolution of single cell RNA-seq (scRNA-seq) found a correlation of NF-YAl with Cancer Associated Fibroblasts (CAFs) and p-EMT cells, a population endowed with metastatic potential. We conclude that overexpression of HFD subunits and NF-YAs is protective in HPV-positive tumors; expression of NF-YAl is largely confined to mutp53 tumors and malignant p-EMT cells.